title: An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with Alzheimer disease.
abstract: Neurofibrillary tangles, one of the hallmarks of Alzheimer disease (AD), are composed of paired helical filaments of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD. We used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes Ser(P)-202, Thr(P)-231, Ser(P)-235, and Ser(P)-396/404) were measured in cell lysates using AlphaScreen assays. GSK3α, GSK3β, and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all four epitopes. We further dissected the effects of GSK3α and GSK3β using pharmacological and genetic tools in hTau primary cortical neurons. Pathway analysis of the kinases identified in the screen suggested mechanisms for regulation of total tau levels and tau phosphorylation; for example, kinases that affect total tau levels do so by inhibition or activation of translation. A network fishing approach with the kinase hits identified other key molecules putatively involved in tau phosphorylation pathways, including the G-protein signaling through the Ras family of GTPases (MAPK family) pathway. The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies.
authors.affiliation: Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, United Kingdom.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Cavallini
authors.forename: Suzanne
authors.initials: S
authors.lastname: Brewerton
authors.forename: Amanda
authors.initials: A
authors.lastname: Bell
authors.forename: Samantha
authors.initials: S
authors.lastname: Sargent
authors.forename: Sarah
authors.initials: S
authors.lastname: Glover
authors.forename: Clare
authors.initials: C
authors.lastname: Hardy
authors.forename: Roger
authors.initials: R
authors.lastname: Moore
authors.forename: John
authors.initials: J
authors.lastname: Calley
authors.forename: Devaki
authors.initials: D
authors.lastname: Ramachandran
authors.forename: Michael
authors.initials: M
authors.lastname: Poidinger
authors.forename: Eric
authors.initials: E
authors.lastname: Karran
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.forename: Philip
authors.initials: P
authors.lastname: Szekeres
authors.forename: Suchira
authors.initials: S
authors.lastname: Bose
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000939:Epitopes; C054369:MAPT protein, human; C558298:Mapt protein, mouse; D016875:tau Proteins; D048292:Mitogen-Activated Protein Kinase 13; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer Disease; Bioinformatics; Enzymes; Glycogen Synthase Kinase 3; Kinase; Phosphorylation; Tau